Drugs containing a psoralene derivative

ABSTRACT

This invention relates to improvements to drugs containing as an active substance the 5-methoxypsoralene of formula: ##STR1##

This is a continuation of application Ser. No. 161,360, filed Feb. 22,1988, now abandoned, which is a continuation of application Ser. No.822,952, filed Jan. 27, 1986, now abandoned which is a continuation ofapplication Ser. No. 498,275, filed May 26, 1983, now abandoned.

FIELD OF THE INVENTION

This invention relates to improvements to drugs containing as an activesubstance the 5-methoxypsoralene of formula: ##STR2##

BACKGROUND OF THE INVENTION

French Pat. No. 77.31719 filed on Oct. 21, 1977 in the name of thepresent Applicant disclosed these new drugs as having a very hightherapeutic index due to the very low toxicity of 5-methoxypsoralenecompared to that of other psoralenes. The patent made clear that onecould use therapeutic doses of 5-methoxypsoralene up to five timesgreater than those used for the 8-methoxypsoralene and advocated theadministration of oral doses of 20 mg to 300 mg of 5-methoxypsoraleneper day, followed by a daily exposure to A ultraviolets, at a rate of1.5 to 10 joules/cm².

For topical administration, the patent advocated 5-methoxypsoraleneconcentrations between 100 ppm and 1000 ppm. The experimentations of thetherapeutical activity of the new drugs had been carried out in thetreatment of psoriasis, vitiligo, atypical eczema and mycosis fungoides.

It should be recalled here that the mycosis fungoides is a well knownskin cancer of the lymphoma type, that is characterized by theproliferation of the lymphocyte cells more present in the lymph, that isthe interstitial liquid irrigating notably the dermis and epidermis. Theclinical experimentations which resulted in Pat. No. 77 31719 had beenof course applied both on patients affected with psoriasis and patientsaffected with skin cancer, since one and the other of said illnesses arecharacterized by a more rapid than normal proliferation phenomenon ofthe cutaneous cells. Such a phenomenon of a too rapid proliferation ofthe cells is at the level of the deoxyribonucleic acid molecule presentin the cell nucleus.

But it is known that the 5-methoxypsoralene, under the energetic actionof a UV.A radiation gets fixed on each of the two helixes of the DNAmolecule and therefore blocks any transmission of the message along saidhelixes, thereby stopping altogether the proteine synthesis and thecellular multiplication. In the normal cells, said blocking of the DNAhelixes is cought up in speed by the DNA self-repair phenomena either byexcision or by replication.

But in the case of cells affected with psoriasis or cancer, that iscells where the multiplication phenomena are very accelerated, theself-repair systems do not have time to set to work. In the same cellshowever the psoralene, by forming bridges between the two DNA helixes,stops the anarchical cellular multiplication. This explains that the5-methoxypsoralene does not disturb in any way the multiplication of thenormal cells and blocks selectively the diseased cells with acceleratedproliferation which are the psoriatic cells and the cancerous cells.

THE INVENTION

After the satisfactory results obtained with the treatment of themycosis fungoides lymphoma (cancer of the lymph cells) by administrationof 5-methoxypsoralene and UV.A exposure, the Applicant had the idea ofcarrying on with investigations on other types of cancers orpre-cancerous lesions of the skin, that is proliferation tumors of theepidermic cells and no more the proliferation of the cells of theinterstitial liquid such as the baso-cellular epithelioma, thespino-cellular epithelioma, the Hutchinson freckles, the actinichyperkeratosis, the cutaneous melanomas, etc.

Such an idea was contrary to the well established general preconceivedidea that the therapy associating the 5-methoxypsoralene and the UV.Aradiation was totally inadvisable in the case of epidermal profilerationtumors, since it was the solar radiation which was producing suchtumors.

It is therefore quite unexpectedly that the Applicant found out that the5-methoxypsoralene could heal epidermal proliferation cancerous tumorswhen administered under new and special conditions, notably as regardsposology.

The pharmacological activity of the drug was brought to the fore bytopical administration of 5-methoxypsoralene on mice having canceroustumors produced by ultraviolets.

It appeared that the 5-methoxypsoralene necessary concentrations of thetopical preparations used were very high: from 10 to 100 times more thanthe previously used concentrations, and this as a function of theexcipient.

The general toxicity of the topical preparations having 1,000 to 10,000ppm of 5-methoxypsoralene has been studied on the mouse with variousexcipients, and has shown that the active substance was well tolerated,even at such high doses. This corresponds to the fact the5-methoxypsoralene is far less toxic than the 8-methoxypsoralene.

For this topical administration of 5-methoxypsoralene, various carriershave proved satisfactory. The hereafter examples are given by way ofillustrations and are not limiting:

the pure petrolatums of various viscosities of the Codex,

the modified petrolatums as the salycilated petrolatum,

mineral oils,

vegetable oils, particularly the ethylenic oils comprising a smallnumber of double bonds,

lanoline,

oily continuous phase emulsions,

alcoholic solutions, etc.

Due to the powerful barrier developped by the cancerous cells withregards to their environment, and notably the thickening phenomenon ofthe cellular membranes, the penetration of the drug by the topical routeis slow and difficult.

According to the invention, it has been found that it was advantageousto introduce in the 5-methoxypsoralene topical preparation penetrationagents such as:

the isopropyl myristate,

the dimethyl sulphoxide (DMSO), etc.

The following clinical experimentations have been carried out withpreparations containing 10,000 ppm pf 5-methoxypsoralene in purepetrolatum.

All volontary patients (a hundred about of them) had family antecedentsand personal antecedents of a skin cancer. They all had had previouslymany ablations of skin cancers, and all the prior treatemnts had notchecked the formation of recurrent cancers.

The types of cancers or pre-cancerous lesions of these patients whichhad been histologically proved were the following:

baso-cellular epitheliomas,

spino-cellular epitheliomas,

Hutchinson speckles,

actinic hyperkeratoses.

Some of these patients showed bilateral effects on the body or limbsallowing subjecting a lateral area to the treatment and keeping theother as a reference.

All the patients chosen had otherwise no serious illness.

All patients have been treated for five weeks in the following manner:

Twice a week, a pure petrolatum based preparation containing 10,000 ppmof 5-methoxypsoralene was applied on the tumor and on its sound closeperiphery (1 to 2 cm beyond the clinically evaluated limit of thetumor). From one to three hours after this application, the patient wassubjected to an UV.A exposure with an energy of 5 joules/cm² to 10joules/cm² (at the end of the treatment) after having reapplied theproduct a quarter of an hour prior to the exposure. The irradiation wasapplied to the whole area on which had been applied the5-methoxypsoralene preparation.

The results were the following: the biopsies carried out at the end ofthe treatment, that is from the sixth week and later, showed a totalnecrosis of the tumor cancerous cells (as well as a healing up of thenormal tissues).

New biopsies were carried out every six months following the treatmentand showed no sign of recurrent or residual illness over a period ofthree years.

The tolerance to the drug and irradiation was perfect, that is withoutmajor phototoxic incident causing a prolongated stop of the treatment.Localized actinic erythemas, rapidly regressive, appeared on somepatients who had a higher sensibility due mainly to their type of skin.

It should be remarked in this respect that the patients thus treatedwith total success had generally types of skin of the so-called type I,that is particularly liable to the skin cancers and notably tophototoxic incidents.

In other clinical experimentations on the same types of epidermicproliferation tumors, the treatment consisted in a topicaladministration of the 5-methoxypsoralene with concentrations of 1,000 to10,000 ppm, doubled by an oral administration of tablets containing5-methoxypsoralene and a UV.A exposure with an average energy of 5joules/cm². There again the results were spectacular and showed thetotal necrosis of the cancerous cells.

The daily posology for the oral treatment of the cancerous tumors canreach 400 to 800 mg of 5-methoxypsoralene due to the low toxicity of thelatter. It is always preferable to increase the dosis of activesubstance rather than the quantity of energy distributed so that theUV.A exposure should remain always within the range of 10 joules/cm².

In the case of cancerous tumors on the mucous membranes accessible bythe natural routes, the treatment such as hereabove described isdirectly applicable, being understood that the UV.A radiation ispenetrating to the very depth of the dermis. In the case of innercancerous tumors, the administration of 5-methoxypsoralene has to befollowed by an exposure to a more penetrating radiation with appropriatewave-lengths in order to bring the necessary energy to the deep sites.

I claim:
 1. A method for the treatment of skin conditions selected fromthe group consisting of carcinomas of the epidermic cells, Hutchinsonfreckles, actinic hyperkeratoses and combinations thereofcomprising:applying topically on the affected skin of a patent in needof such treatment from 1,000-10,000 ppm of 5-methoxypsoralene in apharmaceutically acceptable carrier; after said application, subjectingthe treated area to ultraviolet A radiation having an energy of 5jules/cm² -10 joules/cm².
 2. A method for the treatment of skinconditions selected from the group consisting of carcinomas of theepidermic cells, Hutchinson freckles, actinic hyperkeratoses, andcombinations thereof, said method comprising:administering to patientsin need of such care by oral route 400-800 mg of 5-methoxypsoralene in atherapeutically acceptable carrier daily; subjecting the affected skinarea to ultravoilet A radiation having a energy of 5-10 joules/cm².
 3. Amethod for the treatment of melanoma comprising:applying topically onthe affected skin of a patient in need of such treatment an amount of5-methoxypsoralene ranging from in excess of 1000 and up to 10,000 ppmin a pharmaceutically acceptable carrier; after said application,subjecting the treated skin to ultraviolet A radiation having an energywithin the range of 5-10 joules/cm².